Neuropsychiatric symptoms (NPS) occur in high rates in Alzheimer's disease (AD;98%), as well as in the early stages of AD, mild cognitive impairment (MCI, over 50% in most studies). NPS are a major predictor of dementia transition. Since MCI is an early stage of AD, for most individuals, treatment of NPS in MCI might delay progression to dementia. To maximize the benefit from disease-modifying therapies for AD, individuals must be identified and treated in the early stages, such as MCI, to prevent progressive, widespread neuropathology and progression of cognitive deficits and NPS. The development of molecular imaging methods to visualize beta-amyloid deposition (AbetaD) in vivo provides an unprecedented opportunity to test mechanistic hypotheses of the neurobiology of early stage AD derived from human post-mortem data and transgenic amyloid mouse models. The importance of studying the consequences of AbetaD is underscored by several lines of evidence that A2D may be necessary but not sufficient to account for NPS or dementia transition. AbetaD associated serotonin (5-HT) degeneration may be an early neurobiological substrate for NPS and may represent a therapeutic avenue to delay progression from MCI to dementia by targeting NPS. Relative to other molecular targets, there is stronger evidence for AbetaD associated 5-HT degeneration, for 5-HT degeneration in MCI and AD and for a role of 5-HT in both cognitive deficits and NPS. Furthermore, 5-HT compounds are the only agents with promising preclinical evidence for multiple mechanisms of prevention and symptomatic treatment, including blockade of amyloid precursor protein processing or AbetaD, synaptic plasticity and improvement in both cognitive deficits and NPS. The proposed longitudinal molecular imaging study will test a neurobiological model of cognitive deficits, NPS and the relationship to global functional decline in normal aging and MCI. Amnestic, multi-domain, MCI (aMCI-MD) participants and normal controls, will undergo longitudinal clinical, cognitive evaluations and high resolution PET scans with well-established radiotracers for 5-HT transporter availability (5-HTT) and AbetaD. Preliminary data in both geriatric depression and aMCI-MD showed lower 5-HTT and greater AbetaD that was more extensive than volume loss and correlated with both cognitive deficits and NPS. The specific aims are: 1. To evaluate 5-HTT, and its relationship to A2D, in aMCI- MD and controls at baseline and longitudinal follow-up and 2. To evaluate 5-HTT and A2D in relation to NPS and cognitive decline in aMCI-MD and controls at baseline and longitudinal follow-up. The hypotheses will be tested that lower baseline and longitudinal reductions in 5-HTT in anterior cortical regions will be associated with higher baseline NPS and worsening of NPS, and combined 5-HTT decrease and AbetaD increase will be associated with greater global functional decline and dementia transition. Having accomplished the specific aims, the data obtained will support future 5-HT pharmacologic intervention studies in aMCI-MD, as well as the investigation of other molecular mechanisms associated with the neurobiological model. PUBLIC HEALTH RELEVANCE: In 2010, 35.6 million people were estimated to be living with dementia worldwide, increasing to 65.7 million by 2030 and 115.4 million by 2050. The proposed studies focus on understanding the neurobiology of neuropsychiatric symptoms (NPS;depression, anxiety, irritability, agitation) and the relationship to cognitive decline in the early stages (mild cognitive impairment, MCI) to inform the development of disease-modifying treatments, which would have a significant impact. Since NPS are a major predictor of dementia transition, understanding the neurobiology of NPS may identify therapeutic targets to delay progression from MCI to dementia by targeting NPS.